IL-1β mediates NGF and COX-2 expression through transforming growth factor-activating kinase 1 in subacromial bursa cells derived from rotator cuff tear patients

• Published in: Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 2019-09, Vol.24 (5), p.925-929
• Main Authors: Nagura, Naoshige, Uchida, Kentaro, Kenmoku, Tomonori, Inoue, Gen, Nakawaki, Mitsufumi, Miyagi, Masayuki, Takaso, Masashi
• Format: Article
• Language: English
• Subjects: Aged; Bursa, Synovial - injuries; Bursa, Synovial - metabolism; Cells, Cultured; Cyclooxygenase 2 - metabolism; Female; Humans; Interleukin-1beta - metabolism; Male; MAP Kinase Kinase Kinases - metabolism; Middle Aged; Nerve Growth Factor - metabolism; Rotator Cuff Injuries - metabolism
• ISSN: 0949-2658; 1436-2023
• DOI: 10.1016/j.jos.2019.02.006

Increased interleukin (IL)-1β expression in the subacromial bursa (SAB) is associated with severe pain in rotator cuff tears (RCTs). Additionally, transforming growth factor (TGF)-β-activated kinase 1 (TAK1) is essential for cytokine-mediated cascades. TAK1 also regulates the expression of pain-associated molecules such as cycloxygenase-2 (COX-2) and nerve growth factor (NGF) in synovial fibroblasts; however, this regulation in the SAB is not fully understood. SAB samples were harvested from 18 subjects with RCTs. The expression and localization of NGF and COX-2 was determined using polymerase chain reaction (PCR) analysis and immunohistochemistry. Regulation of COX-2 and NGF by IL-1β in subacromial bursa cells (SABCs) was investigated by culturing and stimulating SABCs with vehicle control (culture medium), 50 ng/ml recombinant human IL-1β (rhIL1-β), 50 ng/ml rhIL-1β and 10 μM celecoxib (COX-2 inhibitor), or 10 μM prostaglandin E2 (PGE2) for 24 h. The effects of TAK1 inhibition on rhIL-1β stimulation were determined by culturing and treating SABCs with control, 50 ng/ml rhIL-1β, or 50 ng/ml rhIL-1β and 10 μM (5Z)-7-oxozeaenol (TAK1 inhibitor) for 24 h. NGF and COX-2 mRNA expression was monitored using quantitative PCR. COX-2 and NGF mRNA expression was observed in all SAB specimens. Immunohistochemical analysis showed that COX-2-positive cells were in the lining and sublining layers. NGF-positive cells were observed in the sublining layer. rhIL-1β treatment significantly increased NGF and COX-2 mRNA levels compared with control cells. The COX-2 inhibitor did not suppress rhIL-1β-induced NGF expression, and PGE2 stimulation did not alter NGF mRNA expression. In contrast, the TAK1 inhibitor significantly reduced rhIL-1β-stimulated COX-2 and NGF mRNA expression. IL-1β regulates the expression of NGF and COX-2, pain-related molecules in the SAB, through TAK1. Therefore, TAK1 may be one potential therapeutic target for reducing pain in patients with RCTs.